Glass Box and Black Box Machine Learning Approaches to Exploit Compositional Descriptors of Molecules in Drug Discovery and Aid the Medicinal Chemist

Abstract

The synthetic medicinal chemist plays a vital role in drug discovery. Today there are AI tools to guide next syntheses, but many are “Black Boxes” (BB). One learns little more than the prediction made. There are now also AI methods emphasizing visibility and “explainability” (thus explainable AI or XAI) that could help when “compositional data” are used, but they often still start from seemingly arbitrary learned weights and lack familiar probabilistic measures based on observation and counting from the outset. If probabilistic methods were used in a complementary way with BB methods and demonstrated comparable predictive power, they would provide guidelines about what groups to include and avoid in next syntheses and quantify the relationships in probabilistic terms. These points are demonstrated by blind test comparison of two main types of BB methods and a probabilistic “Glass Box” (GB) method new outside of medicine, but which appears well suited to the above. Because many probabilities can be involved, emphasis is on the predictive power of its simplest explanatory models. There are usually more inactive compounds by orders of magnitude, often a problem for machine learning methods. However, the approaches used here appear to work well for such “real world data”.